THE PRESENILINS AS G-PROTEIN COUPLED RECEPTORS Our evidence (1,2) for a 7-TM structure for the Presenilins (PS) has led us to question whether PS-1 and PS- 2 belong to the GPCR superfamily of proteins, which all share essentially a similar structure. Previous work by others (3) has shown G-protein activation by PS-1, although these findings have been ignored, presumably because the 8-TM structure of the presenilins has been nearly universally accepted by the field over the last several years. Our hypothesis is that in such a system, the activation of PS would lead to G- protein binding, which in other systems, modulates many downstream signaling events. Regulation of the proposed GPCR function of PS-1 and PS-2 may therefore have consequences for Alzheimer's disease. Our specific aims are as follows: 1. To further confirm and extend the molecular details of G-protein binding to PS-1 and PS-2 (the latter not having been previously studied). 2. To investigate whether the GPCR function of PS-1 and PS-2 modulates the Ca2+ homeostasis that is frequently perturbed in the cell in Alzheimer's disease. 3. To investigate a possible role of membrane-bound B-APP as a specific ligand for PS-1 and PS-2 that regulates their GPCR activity, both in connection with normal cell physiology, and with the mechanisms involved in the etiology of Alzheimer's disease. Relevance to Public Health: Significance for Alzheimer's Disease: If our proposed studies elucidate Presenilin:G-protein coupling to indeed be significant to the mechanism by which PS mediates Ca2+ homeostasis in Alzheimer's disease, or/and they show that [unreadable]-APP is the ligand that specifically activates PS-Go coupling, then a possible outcome of these studies might be a drug therapy for Alzheimer's disease using appropriately designed inhibitors of PS-Go specific binding.